N-substituted-alpha,alpha,alpha-trifluoro-m-toluamides

ABSTRACT

DISCLOSED ARE A,A,A-TRIFLUORO-M-TOULAMIDES WHEREIN THE N IS SUBSTITUTED WITH GROUPS SUCH AS DI(LOWER)ALKYLAMINO(LOWER)ALKYL, MOROPHOLINO(LOWER)ALKYLAMINO, N-SUBSTITUTED-3 OR 4-PIPERIDYLAMINO, PIPERIDINO(LOWER)ALKYLAMINO AND N-SUBSTITUTED-1,3 OR 1,4-HEXAHYDRO-1-H-DIAZEPINE. THE COMPOUNDS DISCLOSED POSSESS UTILITY AS CENTRAL NERVOUS SYSTEM DEPRESSANTS USEFUL IN CLAMING ANIMALS.

United States Patent 3,787,419 N-SUBSTITUTED-m,a,u-'IRIFLUOR0-m-TOLUAMIDES William F. Bruce, Havertown, Pa., assignor to American HomeProducts Corporation, New York, N.Y. No Drawing. Filed July 1, 1971,Ser. No. 159,059 Int. Cl. C07d 29/28, 29/30, 41/08 US. Cl. 260-29337 1Claim ABSTRACT OF THE DISCLOSURE Disclosed area,a,u-trifluoro-m-toluamides wherein the N is substituted with groupssuch as di(lower)alkylamino- (lower)alkyl, morpholino(lower)alkylamino,N-substituted-3 or 4-piperidylamino, piperidino(lower)alkylamino andN-substituted-1,3 or 1,4-hexahydro-1-E-diazepine. The compoundsdisclosed possess utility as central nervous system depressants usefulin calming animals.

This invention relates to new and novel toluamides. Particularly, itrelates to new and novel ot,ot,at1ifll.l01'0- m-toluamides. Moreparticularly, this invention relates to compounds having the formula:

wherein A is selected from the group consisting of:

wherein B is (lower)alkylene of from 2 to about 6 carbon atoms; R and Rare selected from the group consisting of hydrogen and (lower) alkyl; Ris selected from the group consisting of hydrogen, phenyl, (lower)alkyland a,a,a-trifiuoro-m-toluoyl; R R and R are selected from the groupconsisting of hydrogen, phenyl and (lower) alkyl; and the non-toxicpharmaceutically acceptable acid addition salts thereof.

When used herein, the term (lower)alkyl and the like contemplateshydrocarbon radicals, straight and branched chain, containing from about1 to about 6 carbon atoms, and includes methyl, ethyl, n-propyl,i-propyl, n-butyl, t-butyl, n-pentyl, n-hexyl, Z-methylpentyl and thelike. The term (lower)alkylene contemplates straight chain hydrocarbonradicals, containing from about 2 to about 6 carbon atoms, and includesmethylene, ethylene, propylene, butylene, pentylene and hexylene.

The new and novel compounds of this invention, Formula I, are preparedby contacting m-trifluoromethyl- Patented Jan. 22, 1974 benzoyl fluoridewith an amino compound of formula HA according to the reation scheme:

C F; C F:

ii If o--r HA Q-C-A (II) (111) (I) wherein A is as defined hereinabovepreviously. In practicing the process described above, substantiallyequimolar mixture of reactants is admixed in a reaction inert organicsolvent for a time period ranging up to about twenty hours. The reactionnormally proceeds at room temperature; however, heating, such as on asteam bath, will at times aid the reaction. The resulting compounds ofFormula I are recovered by routine procedures, i.e., washing with waterand recrystallizing the precipitate so formed. The expression reactioninert organic solvents, as used herein, refers to organic solvents whichdissolve the reaction components without interfering with the reaction.All temperatures referred to herein and in the appended claims are indegrees Celsius unless otherwise indicated. The starting materials ofFormulae II and 111 are commercially available or may be provided bymethods readily available to those skilled in the art.

In accord with the present invention, the m-(trifluoromethyl)toluamidesof Formula I of the present invention have been found to possessinteresting pharmacological properties. More particularly, thesecompounds, in standard pharmacological tests, have exhibited utility ascen tral nervous system depressant agents which are useful in producinga calming effect on animals.

In the pharmacological evaluation of the central nervous systemdepressant compounds of Formula I of this invention the in vivo effectsof the compounds of this invention are tested as follows:

The compound is administered intraperitoneally and/ or orally to threemice (14 to 24 grams) at each of the following doses: 400, 127, 40 and12.7 trig/kg. The animals are watched for a minimum of two hours duringwhich time signs of general stimulation (i.e., increased spontaneousmotor activity, hyperactivity on tactile stimulation, twitching),general depression (i.e., decreased spontaneous motor activity,decreased respiration) and autonomic activity (i.e., miosis, mydriasis,diarrhea) are noted. The animals are tested for changes in reflexes(i.e., flexor, extensor) and are rated by use of a pole climb andinclined screen for the presence of sedation-ataxia. The Eddy Hot-PlateMethod [Nathan B. Eddy and Dorothy Leimbach, J. Pharmacol. Exper.Therap. 107,385 (1952)] is used to test for analgesia. The experiment isterminated by subjecting each animal to a maximal electroshock to testfor anti-convulsant activity.

The compounds of Formula I of this invention, when administeredintraperitoneally in the above test procedure, induce decreased motoractivity at a range of 12.7 mg./kg. to 400.0 mg./kg. Similar results areobtained when these compounds are administered orally at a range of 40mg./ kg. to 400.0 mg./kg.

When the compounds of this invention are employed as central nervoussystem depressant agents to produce a calming efiect, they may beadministered to warm-blooded animals, e.g., mice, rats, rabbits, dogs,cats, monkeys, etc. alone or in combination with pharmacologicallyacceptable carriers, the proportion of which is determined by thesolubility and chemical nature of the compound, chosen route ofadministration and standard biological practice. For example, they maybe administered orally in the solid form containing such excipients, asstarch, milk sugar, certain types of clay and so forth. They may also beadministered orally in the form of solutions or they may be injectedparenterally. For parenteral administration, they may be used in theform of a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present central nervous system depressants will varywith the form of administration and the particular compound chosen.Furthermore, it will vary with the particular subject under treatment.Generally, treatment is initiated with small dosages substantially lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. In general, the compounds of this inventionare most desirably administered at a concentration level that willgenerally afford eifective results without causing any harmful ordeleterious side effects.

The following examples are given by way of illustration and are not tobe construed as limitations of this i vention, many variations of whichare possible without departing from the scope and spirit thereof.

EXAMPLE I N- (Z-dimethylaminoethyl) -u,a,ot-trifluoro-mtoluamide andmaleate To a solution of 5 g. of N,N-dimethylaminoethylamine in fiftyml. of dimethylformamide (DMF) and ml. of triethylamine is addeddropwise 9.5 g. of m-trifluoromethylbenzoyl fluoride. After standingovernight, the mixture is diluted with five volumes of water to give anoil heavier than water. This is taken up in ether, the ether washed withwater and dried over potassium carbonate. It is then neutralized byaddition of maleic acid in ether. This gives an oil which crystallizeson seeding to give g. of white stubby needles, M.P. 106-107".

Analysis.-Calcd. fOI C15H19F3N205 (percent): C, 51.06; H, 5.09; N, 7.45.Found (percent): C, 50.96; H, 5.04; N, 7.41.

EXAMPLE II N-(2-diethylaminoethyl)-a,a,u-trifluoro-m-toluamide CHaCH;

EXAMPLE III a,a,a-Trifluoro-N- 2-morpholinoethyl)-m-toluamide To asolution of 6.5 g. of N-(B-aminoethyDmorpholine in ml. of DMF and 7 ml.of triethylamine is added 9.5 g. of m-trifluoromethylbenzoylfluoride in20 ml. of DMF, in small portions with shaking. After an hour on a steambath, the solution is diluted with four volumes ofu,uz,a-trifluoromethyl-N- 6-morpholinohexyl) -mtoluamide;a,a,a-trifluoromethyl-N- 4-morpholinobutyl) -mtoluamide; a,u,a-trifiuoromethyl-N- (3-morpholinopropyl -mtoluamide.

EXAMPLE IV N- [2- (diisopropylamino) ethyl] -u, 0:,ot-tlifltl0l0-m-toluamide and perchlorate To a solution of 7 g. ofdiisopropylaminoethylamine in ml. of ether and 9 ml. of triethylamine isadded 8 g. of m-trifluoromethylbenzoylfluoride. After two hours ofstirring, ml. of water is added and 15 ml. of 50% sodium hydroxide. Theether layer is separated and concentrated on a steam bath in a currentof air to remove triethylamine. The residue in ether is neutralized with60% perchloric acid to give 13 g. of crystalline product, M.P. 121-122,recrystallized from ethanol to give 10 g. of yellowish-white crystals,M.P. 121-122.

Analysis.Ca1cd. for C H ClF N O (percent): C, 46.09; H, 5.08; Cl, 8.51;F, 13.68; N, 6.72. Found (percent): C, 46.16; H, 5.87; Cl, 8.5; F, 13.8;N, 6.85.

EXAMPLE V N -[2- (diisobutylamino)ethyl]-a,a,atrifiuoro-m-toluamide C F:0 /CH G Q-PJ-NHCHiCHaN CH /OH:

CHaCH To a solution of 8 g. of diisobutylaminoethylamine in 80 ml. ofabsolute ether is added dropwise 8 g. ofm-trifluoromethylbenzoylfluoride with stirring and cooling. Aprecipitate appears at once but dissolves before half the acid fluorideis added. The ether solution is washed with sodium carbonate solutionand concentrated to give an orange oil which solidifies on cooling andgives 12.5 g. of white felt-like needles upon crystallization from 80%ethanol; M.P. 80-81.

Analysis.-Calcd for C H F N O (percent): C, 62.77; H, 7.90; F, 16.55; N,8.14. Found (percent): C, 62.76; H, 8.08; F, 16.8; N, 8.09.

EXAMPLE VI N- 3- (di-n-butylamino) propyl] mega-trifiuoro-m-toluamide Toa solution of 9.5 g. of di-n-butylaminopropylamine in 50 ml. of absoluteether is added 9.5 g. of m-trifluoromethylbenzoylfluoride in 25 ml. ofabsolute ether, dropwise, with cooling and stirring. After the solutionstands overnight, it is washed with 100 ml. of water, which is extractedwith ether, all the ether extracts are combined, dried over potassiumcarbonate, and concentrated to give 15 g. of oil which is distilled,giving 12 g. of very pale yellow product, boj 180185.

Analysis.Calcd. for C H F N O (percent): C, 63.66; H, 8.16; F, 15.90; N,7.82. Found (percent): C, 63.46; H, 8.27; F, 16.0; N, 7.72.

EXAMPLE VII N- 1-ethyl-3-piperidyl) -oz,a,oc-tliflu0r0- m-toluamide andperchlorate CHzCHfl CF:

To a solution of 6.7 g. of 3-amino-N-ethylpiperidine in 100 ml. ofabsolute ether is added slowly with stirring and cooling a solution of9.6 g. of m-trifluoromethylbenzoylfluoride in 40 m1. of absolute ether,giving a white precipitate which becomes an oil. After standing twodays, the ether solution is treated with 50 ml. of water and madealkaline by addition of sufiicient 40% sodium hydroxide. Upon drying theether layer over potassium carbonate and neutralizing it with 60%perchloric acid, a white crystalline salt appears and is recrystallizedfrom water: g., M.P. 176-177".

Analysis.Calcd. for C H ClF N O (percent): C, 44.95; H, 5.03; F, 14.22;N, 6.99. Found (percent): C, 45.07; H, 4.92; F, 14.1; N, 6.99.

In a similar manner, using the appropriate starting materials, thefollowing compounds are provided:

EXAMPLE VIII a,a,a-Trifiuoro-N-(2-piperidinoethyl)- m-toluamidemonohydrate To a solution of 6.5 g. of 2-piperidinoethylamine in 100 ml.of absolute ether is added dropwise with stirring and cooling a solutionof 8.6 g. of m-trifluoromethylbenzoylfluoride in ml. of absolute ether.After the mixture stands overnight it is treated with 50 ml. of waterand made alkaline by addition of suflicient 40% sodium hydroxide.Concentration of the ether solution gives an oil which crystallizes fromethyl acetate-hexane to give 6 g. of shiny yellow platelets, M.P. 61-62.

Analysis.-Calcd. for C H F N O (percent): C, 56.59; H, 6.65; F, 17.91;N, 8.80. Found (percent): C, 56.58; H, 6.86; F, 17.9; N, 9.00.

In a similar manner, using the appropriate starting materials, thefollowing compounds are provided:

a, a,a-tri.fluoromethyl-N- (4-piperidinobutyl -m-toluamide;u,a,e-trifluoromethyl-N-(3-piperidinopropyl)- m-toluamide.

6 EXAMPLE 1x N- [2- (dib utylamino ethyl] -oz,a,ot-tllfil10f0-m-toluamide and maleate I hNHomornN CHzCHgCHzCHa To 5 g. of2-di-n-butylaminoethylamine in 130 ml. of absolute ether is added 6 g.of m-trifluoromethylbenzoylfluoride in 20 ml. of absolute ether withcooling and shaking. After standing overnight, the solution is washedwith dilute sodium hydroxide, the ether dried over potassium carbonate,and acidified with a solution of maleic acid in ether. The light yellowoil which separates solidifies upon being scratched and isrecrystallized from methyl acetate-heptane to give 6.5 g. of very lightflutfy white crystals, M.P. 91-92.

Analysis.--Calcd. for C H N F O (percent): C, 57.38; H, 6.79; F, 12.38;N, 6.09. Found (percent): C, 57.46; H, 6.99; F, 12.4; N, 6.32.

EXAMPLE X u,a,a-Trifluoro-[4-(diisopropylamino)butyl]- m-toluamide /CHaCF: 0 CH\ 4% CH2 NHCH2CH2CH2CH2N /CHa EXAMPLE XI a,a,a-trifluoro-N- (2-[4- a,a,u-trifluoro-m-toluoyl) piperazino]ethyl)-m-toluamide andhydrochloride O O QaNHCMFN Mt Q A solution of 19 g. ofm-trifluoromethylbenzoylfluoride in 50 ml. of absolute ether is added,dropwise with stirring and cooling, to 6.5 g. ofN-(B-aminoethyDpiperazine in ml. of absolute ether. After standingovernight, the solution is washed with water and dilute sodiumhydroxide, and dried over potassium carbonate. After filtering out asmall amount of fluffy by-product, an ethereal solution of hydrogenchloride is added to give a white solid, 9 g., M.P. 235237;recrystallized from ethanol, this gives 7 g. of flaky white crystals,M.P. 235-236".

Analysis-Calm. for C H ClF N 0 (percent): C, 51.82; H, 4.35; C], 6.95;F, 22.36; N, 8.24. Found (percent): C, 51.94; H, 4.22; CI, 6.9; F, 21.9;N, 8.20.

In a similar manner, using the appropriate starting materials, thefollowing compounds are provided:

a,a,a-trifluoro-N(2-piperazinoethyl)-m-toluamide;

a, u,a-trifluoro-N- (4-phenyl-2-piperazinoethyl) -m toluamide;

oz,oz,oc-trlfiuO1'O-N- (4-propyl-3-piperazinopropyl -mtoluamide;

7 N- (4-ethyl-4-piperazinobutyl -a,a,u-trifluoro-mtoluamide;N-(4-ethyl-2-piperazinoethyl)-a,u,u-trifluoro-mtoluamide.

EXAMPLE XII 1-methyl-4-(a,a,a-trifluoro-m-toluoyl)piperazine andhydrochloride C F: O Gan ME.

A solution of 10 g. of m-trifluoromethylbenzoylfluoride in 30 ml. ofabsolute ether is added dropwise with shaking and cooling to 6 g. ofN-methylpiperazine in 80 m1. of absolute ether. After standingovernight, the solution is washed with dilute sodium hydroxide and theether layer, dried over potassium carbonate, and acidified with etherealhydrogen chloride to give 11 g. of white crystals, M.P. 285

-with sublimation. Recrystallization from methanol gives 8 g. of powderywhite solid, M.P. 285-286 with sublimation.

Analysis-Gabi for C H ClF N O (percent): C, 50.57; H, 5.22; C1, 11.49;F, 18.46; N, 9.08. Found (percent): C, 50.59; H, 5.08; Cl, 11.5; F,18.6; N, 9.13.

In a similar manner, using the appropriate starting materials, thefollowing compounds are prepared:

4- a,a,a-trifluoro-m-toluoy1) piperazine;

4- ma,a-trifiuoro-m-toluoyl) piperazine sulfate; 1-ethy1-4-u,a,a-trifiuoro-m-toluoyl piperazine; l-pentyl-4- m,a,x-trifluoro-m-toluoyl)piperazine.

EXAMPLE XIII 1-phenyl-4- (a,m,a-trifluoro-m-toluoyl) piperazine andhydrochloride A solution of 10 g. of m-trifluoromethylbenzoylfluoride in20 ml. of absolute ether is added, dropwise with stirring and cooling,to 8.1 g. of N-phenylpiperazine in 100 m1. of absolute ether. Afterstanding overnight, the solution is washed with dilute sodium hydroxideand the ether solution, dried over potassium carbonate, is acidifiedwith ethereal hydrogen chloride to give 22 g. of white solid, M.P.171-172". Recrystallization from ethanol gives 14 g. of white granularcrystals, M.P. 172173.

Analysis.Calcd. for; C H F N Ol-lclz C, 58.30; H, 4.89; Cl, 91.56; F,15.37; N, 7.56. Found: C, 58.41; H, 4.75; Cl, 9.5; F, 15.5; N, 7.87.

8 EXAMPLE Xrv Hexahydro 1 methyl-4-(u,u,a-trifluoro-m-toluoyl-l-H-1,4-diazepine and hydrochloride A solution of 10 g. ofm-trifiuoromethylbenzoylfiuoride in 20 ml. of absolute ether is added,dropwise with cooling and shaking, to 6 g. of N-methylhomopiperazine in100 m1. of absolute ether. After standing overnight, this mixture iswashed with dilute sodium hydroxide. The ether, dried over potassiumcarbonate, is acidified with ethereal hydrogen chloride to give an oilwhich becomes solid on standing and seeding. Recrystallization fromethanol gives 9 g. of white microcrystals, M.P. 214-215.

Analysis.Calcd. for C H ClF N 0 (percent): C, 52.10; H, 5.62; Cl, 10.98;F, 17.66; N. 8.68. Found (percent): C, 52.00; H, 5.85; Cl, 11.1; F.17.9; N, 9.04.

In a similar manner, using the appropriate starting materials, thefollowing compounds are provided:

3-(a,m,a-trifluoro-m-toluoyl) hexahydro-l g-lj-diazepine sulfate;

4-(a,u,a-trifiuoro-m-toluoyl) hexahydro-1 phenyl-I -I- 1,4-diazepine;

1-ethyl-3-(a,u,a-trifiuoro-m-toluoyl)-hexahydro-1 4,3-

diazepine;

3-(a,a,a-trifiuoro-m-toluoyl) hexahydro-l-phenyl l-g- 1,3-diazepine;

4-(oc,oc,oc trifiuoro-m-toluoyl)-hexahydro-1-pentyl-1 H- 1,4-diazepine.

What is claimed is: 1. N-(1-ethy1-3-piperidyl)-u,a,u-trifiuoro-mtoluamideperchlorate.

References Cited UNITED STATES PATENTS 2,748,134 5/1956 Stoll et a1260-29177 3,647,805 3/1972 Irikura et a1 260-293.77 2,785,200 3/1957Moore 260558 D 3,177,252 4/ 1965 Thominet 260-293.77 3,502,652 3/1970Jucker et a1 260-239 B C 3,509,166 4/1970 Wright et a1 260-558 R OTHERREFERENCES Johnson et al., Chem. Abstracts, vol. 70, Abstract No. 28589t(1969). QDIASI.

AITON D. ROLLINS, Primary Examiner US. Cl. X.R.

260-239 BC, 247.2 A, 251, 268 R, 268 c, 268 PH, 558 R; 424-244, 248,250,251, 267, 324

